tbuckley/cabot-search huggingface dataset:
Association of<i> TP53</i> mutations with the expression of PD-L1 expression and TMB, and R175H could be the predictor of neoantigen.
Authors: Lucas Wang, Yaxian Yang, Heran Wang, WenTao Fan, Bin Lian, Ying Jin, Weiquan Luo, Zhongming Long, Mingming Huang, Yongsi Wang, Yunjie Wen, Jian Huang
Journal: Journal of Clinical Oncology (2023)

e20530 Background: Lung cancer (LC) is the second leading causes of cancer-related mortality and composed of diverse molecular types. PD-L1 expression and tumor mutation burden (TMB) are important biomarkers of tumor immunotherapy. TP53 mutation is associated with neoantigen productions which is also involved in tumor immunotherapy. The relationship between PD-L1 expression, TMB and TP53 mutations have not yet been fully studied, and the neoantigens derived from TP53 mutations need to be explored. Methods: The total 1932 LC tissue samples (from same number of patients) in formalin fixed and paraffin embedded were collected from Guangzhou Huayin Health Medical Group Co.,Ltd. By targeting next generation sequencing (NGS) of 600 genes, the mutations of TP53 and TMB were obtained. PD-L1 expression was determined according to the tumor proportion score (TPS) evaluated by immunohistonchemistry (the cutoff of PD-L1 is greater than 1% TPS). Neoantigen predictions based on binding affinity data (https://services.healthtech.dtu.dk/service.php?NetMHCcons-1.1). In this data set, mutated peptides of TP53 with a binding affinity of IC50≤50 nM was regarded as candidate neoantigens. Results: Among 1932 samples, 890 (46%) were TP53 mutated. The positive rate of PD-L1 in TP53 mutant type (MT) group was higher than that in TP53 wide type (WT) group(p &lt; 0.01). The WT group had a lower TMB compared with MT group (p = 0.002). The intersection of 49 candidate neoantigens and TP53 high-frequency mutation sites was R175H, which could predicate a neoantigen. Conclusions: This study determined the connection between TP53 mutations and PD-L1 expression and TMB, also made neoantigen prediction of R175H mutation. This study may provide theoretical insights for drug developments of treating lung cancer.
Pre-treatment plasma-informed circulating tumor DNA detection as an early identification of therapeutic benefit for patients with untreated advanced lung squamous cell carcinoma.
Authors: Tao Jiang, Jiao Zhang, Feifei Li, Li-Di Xu, Ting Ma, Ying Yang, Yu S. Huang, Weizhi Chen, Caicun Zhou
Journal: Journal of Clinical Oncology (2023)

9041 Background: Circulating tumor DNA (ctDNA) detection as a promising prognostic factor to assess treatment response has been widely studied with customized tumor-informed strategies, the application of which was limited by the inaccessibility for tumor biopsies in a substantial proportion of patients. To overcome this challenge, we presented a proof-of-concept study for the development of a novel personalized pre-treatment plasma-informed next generation sequencing (NGS) panel and investigated its prognostic value for first line treatment in patients with advanced lung squamous cell carcinoma (LUSC). Methods: Paired plasma and white blood cell (WBC) samples were collected from 227 of stage IIIB-IV LUSC patients who were treated with first line either chemotherapy or chemotherapy plus PD-1 blockade at pre- and post-treatment. Somatic mutations in pre-treatment plasma were identified with a 769-gene based NGS panel (Genecast, Wuxi, China) followed with germline or clonal hematopoietic variants filtering by referring to the WBC samples. Positive variants detected in the pre-treatment plasma served as a basis for personalized variants tracking in post-treatment plasma. ctDNA kinetics was measured by plasmaDelta (Δgenevaf=((post-treatment genevaf – pre-treatment genevaf) / pre-treatment genevaf; genevaf was defined by variant allele frequency for each individual gene). Progression-free survival (PFS) as the primary endpoint and overall survival (OS) as the secondary endpoint were assessed. Results: ctDNA positivity was observed in 80% (182/227) of pre-treatment samples and subsequently 54% (99/182) of post-treatment samples. ctDNA positivity at post-treatment was shown to be a significant predictor for both PFS and OS in the whole group as well in the sub-treatment groups (Table). After adjusting for clinicopathologic variables, ctDNA positivity remained significantly associated with both worse PFS and OS (PFS: HR = 2.3, P &lt;0.001 and OS: HR= 2.56, P &lt;0.001). ctDNA kinetics further identified a worse treatment response group. Patients with high plasmaDelta had remarkably worse outcomes than patients with low plasmaDelta (PFS: HR =4.8; 95%CI=2.8-8.3; P &lt; 0.001 and OS: HR=2.8; 95%CI=1.7-4.6; P &lt;0.001). Conclusions: These results demonstrated the feasibility of pre-treatment plasma-informed ctDNA detection and kinetics for monitoring treatment response in LUSC patients whose tumor biopsies were unavailable. [Table: see text]
Belantamab mafodotin (belamaf) for relapsed/refractory multiple myeloma (RRMM): A real-world observational study update.
Authors: Malin Hultcrantz, David Kleinman, Ravi Vij, Fernando Escalante, Michel Delforge, Nirali Kotowsky, Jacopo Bitetti, Natalie Boytsov, Leena Camadoo-O'Byrne, Lindsey Powers Happ, Mujib Rohman, Guillaume Germain, Mei Sheng Duh, François Laliberté, Malena Mahendran, Ana Urosevic, Hans C. Lee
Journal: Journal of Clinical Oncology (2023)

e20046 Background: A prior retrospective analysis of US patients (pts) with RRMM suggested that pts treated with belamaf, a BCMA-targeting antibody-drug conjugate, experienced similar outcomes to those who received belamaf in the pivotal DREAMM-2 study. This updated analysis aimed to characterize pts, assess occurrence and management of ocular adverse events (AEs), and evaluate belamaf effectiveness in a real-world setting. Methods: This retrospective, longitudinal, observational study used data sourced from the US EHR-derived Flatiron Health de-identified database (01/01/2011–06/30/2022). Eligible pts had a confirmed MM diagnosis, initiated belamaf after FDA approval (08/05/2020; first administration=index date), were ≥18 years old at index, and had chart abstraction data for ocular safety and treatment effectiveness. Data on ocular AEs were reported separately for all pts and pts with ≥4 months (mo) of follow-up to allow for sufficient follow-up to evaluate incidence of ocular AEs and their mitigations. Tumor response was assessed in all pts, along with Kaplan-Meier estimates of duration of response (DoR), overall survival (OS), and progression-free survival (PFS). Results: Of the 184 pts included in the study, mean age was 68.7 years; 64% were White and 47% were female. Eastern Cooperative Oncology Group (ECOG) status was ≥2 in 28% patients, 62% had received ≥5 prior lines of therapy, and 82% were triple-class refractory. Median (IQR) follow-up was 4.1 (1.9–8.5) mo. Among pts with ≥4 months of follow-up (n=94) 75% had ≥1 ocular AE, with keratopathy and blurred vision being the most frequent. Mean (SD) time to first ocular AE was 39 (34) days. Most ocular AEs were managed by therapy hold (69%; of which 73% restarted belamaf) and/or AE treatment (63%). The median dose hold due to ocular AEs was 43 days (physician-reported keratopathy: mild, 21 days; moderate/severe, 56 days). In all pts, 39 (21%) had a derived tumor response based on serum free light chain levels, (partial response: 74%, very good partial response: 51%). For all pts, the estimated median DoR was 9.1 mo, PFS 4.5 mo, and OS 7.9 mo, while the 6-month DoR rate was 57%, PFS rate was 46%, and OS rate was 58%. Conclusions: Overall, belamaf was effective in the real world setting in heavily pre-treated pts with RRMM and limited therapy options. The AE profile was consistent with DREAMM-2. Ocular AEs were manageable and despite their occurrence, a high percentage of pts remained on treatment, suggesting belamaf may fill an unmet need for triple-class refractory pts with RRMM. [Table: see text]
Effects of concomitant chronic obstructive pulmonary disease on immune microenvironment in non-small cell lung cancer patients.
Authors: Lin Lin, Rui Chen, Xiaoling Lin, Sunyongxun Zhuan, Jianguo Li, Xue Hu
Journal: Journal of Clinical Oncology (2023)

e20522 Background: Chronic obstructive pulmonary disease (COPD) as a progressive deterioration of lung function, has caused significant morbidity and mortality, especially in developing countries. Persistent lung inflammation and potential lung stroma remodeling in COPD may be important causes of lung cancer. Previous studies have shown that non-small cell lung cancer (NSCLC) patients with COPD have a worse prognosis than those without, but the reasons have not been determined. Due to the increasing application of ICIs in the NSCLC, the characteristics of the immune microenvironment in the NSCLC patients concomitant COPD are worth exploring. Methods: Immune microenvironment and the next generation sequencing (NGS) data of twenty NSCLC patients from Sun Yat-sen Memorial Hospital were analyzed. Formalin-fixed paraffin-embedded biopsy tissue before first-line treatment to prepare tumor tissue slides. Samples were stained using an Opal automation mIF Detection Kit (Akoya) for immune cells. The immune cell infiltration were reported as percentages and density from each individual cell subpopulation in the tumor or stromal area. The landscape of gene mutantions was obtained by NGS detection of 733-gene panel, sequencing depth was 35000x. Results: There were 8 (40%) patients concomitant COPD, and the median age was 65.5-year-old. Analysis the immune cell infiltration in all patients, including T cells, B cells, macrophages and NK cells through 13 markers, showed no difference between COPD and non-COPD groups. However, comparing the differences between tumor and stromal immune microenvironment, it was found that there was a significant difference in the percentages of M1 macrophages between tumor and stromal in COPD group (P = 0.031), but no difference in non-COPD group (P = 0.47). Further analysis of the difference in cell density between tumor and stroma showed that the stromal M1 macrophages in the COPD group was significantly higher than that in the non-COPD group (P = 0.017), as well as PD-1 + CD8 + T cells (P = 0.05). Additionally, a preliminary analysis of the gene mutation characteristics had done. In COPD patients with somatic mutations, the most frequently mutated gene was EGFR (60%), followed by TP53 (50%) and GLI2 (50%), which were similar as non-COPD patients. The most common variant of COPD patients are the missense mutation of EGFR L858R, but it was EGFR 19del in non-COPD. Conclusions: The results showed that the COPD was correlated with the infiltration status of M1 macrophages and PD-1 + CD8 + T cell, and poor immune cell infiltration in tumor of COPD patients may be the potential influencing factors for the worse prognosis. The characteristics of immune microenvironment suggest that promoting the entry of immune cells from stroma into tumor may be a potential mechanism for the benefit of immunotherapy in NSCLC patients with COPD.
MSH3 and MSH6 gene polymorphisms: Association with lung cancer susceptibility and prognostic value in patients with NSCLC undergoing platinum-based chemotherapy.
Authors: Navneet Singh, Sidhartha Singh, Parul Sharma, Siddharth Sharma
Journal: Journal of Clinical Oncology (2023)

9031 Background: DNA mismatch repair (MMR) pathway is responsible for recognizing and repairing errors (insertion, deletion and misincorporation of bases) occurring during DNA replication and recombination. Single nucleotide polymorphisms (SNPs) in MSH3 and MSH6 genes are related to development of various cancers. SNPs of particular interest include rs26279 G &gt; A polymorphism for MSH3 and rs3136228 557G &gt; T polymorphism for MSH6. In this cohort study, we evaluated the association of MSH3 (rs26279) and MSH6 (rs3136228) SNPs with occurrence of lung cancer (LC), baseline demographic and clinical characteristics and with overall survival (OS) amongst LC patients undergoing platinum-based doublet chemotherapy. Methods: 500 LC patients and 500 healthy controls were enrolled. Genomic DNA was isolated from 4ml of peripheral blood using a phenol-chloroform extraction procedure and genotyping of patients and controls was performed using PCR-RFLP. All enrolled patients had pathologically confirmed LC. Written informed consent was obtained from all enrolled subjects and the study was approved by institutional ethics committee. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using logistic regression analysis. Kaplan-Meier method was used for OS analysis and (multivariate) Cox regression models to obtain (adjusted) hazards ratios (HRs). Results: Mean age (61 years) was similar for cases and controls. Compared to controls, LC cohort had higher prevalence of non-smokers (20% vs. 10%), female sex (20% vs. 9%) and smoking pack-years (mean 20.8 vs. 13.8). Majority of LC patients had metastatic disease (54%) and ECOG performance status of 0-1 (45%) or 2 (40%). Adenocarcinoma and squamous were equi-prevalent (41% each). Mutant genotype (TT) for MSH6 polymorphism was more frequent in LC patients (OR = 1.43; 95% CI = 1.01 – 2.03; p = 0.03) with the association more marked in adenocarcinoma histology (OR = 1.74; 95% CI = 1.05 – 2.93; p = 0.03). For non-smokers, mutant genotype (TT) for MSH6 polymorphism was associated with a 3-fold increased risk of LC (OR = 3.22; 95% CI = 1.26 – 8.18; p = 0.01). Amongst females, heterozygous genotype (GA) for MSH3 polymorphism was more frequent amongst LC cases (24%) than controls (16%) (OR = 2.35, 95% CI = 0.85 – 6.52, p = 0.04). Patients treated with docetaxel-platinum chemotherapy and carrying heterozygous (GT) genotype for MSH6 polymorphism had worse OS (median 4.9 vs 9.1 months; adjusted HR = 2.3; p = 0.03). No association was observed between MSH3 (rs26279) and MSH6 (rs3136228) polymorphisms and other baseline clinical/demographic characteristics. Conclusions: The results of this cohort study suggest that MSH3 and MSH6 polymorphisms are involved in modulating the risk towards LC occurence. MSH6 polymorphism is also associated with higher mortality amongst patients treated with docetaxel-platinum chemotherapy.
Contemporary biomarker testing rates in both early and advanced NSCLC: Results from the MYLUNG pragmatic study.
Authors: Makenzi Colleen Evangelist, James Edward Butrynski, John C. Paschold, Patrick J. Ward, Alexander I. Spira, Kashif Ali, Janet L. Espirito, David Hakimian, Robert M. Jotte, Beth Koselke, Timothy Larson, Michael W. Meshad, Marcus A. Neubauer, Katie Ogden, Rami Owera, Donald A. Richards, Nicholas J. Robert, Jennifer M. Walberg, Yunfei Wang, Robert L. Coleman
Journal: Journal of Clinical Oncology (2023)

9109 Background: The MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) consortium pragmatic study aims to identify and overcome barriers to timely and appropriate biomarker testing in patients (pts) with NSCLC. We previously reported retrospective real-world testing rates for 5 biomarkers from 2018-2020 in metastatic pts. We now report results from the prospective observational phase, including additional biomarkers in pts with both early and advanced NSCLC. Methods: This was a prospective, non-interventional cohort study of newly diagnosed pts with early stage (ES), locally advanced (LA), or metastatic NSCLC (mNSCLC) between 12/2020 and 9/2022 and enrolled from 12 community practices (69 sites) across The US Oncology Network. The proportion of pts with test results for 9 biomarkers at time of protocol initiation were examined: ALK, BRAF, EGFR, ROS1, PD-L1, KRAS, MET, NTRK, and RET. Timing of tests, use of single vs multigene NGS testing, clinical and socioeconomic factors, and reasons for not testing were collected in real time. Results: Of 1002 pts screened, 987 were enrolled and analyzed. There were 405 stage IB-IIIC pts [n = 284 stage IB-IIIA (ES cohort); n = 121 stage IIIB-IIIC (LA cohort)] and 582 stage IV pts (mNSCLC cohort). Descriptions for ES and LA vs mNSCLC pts respectively include median age 68 vs 69 yrs, 49% vs 52% female, 83% vs 77% white, 58% vs 79% adenocarcinoma histology, 71% vs 68% ECOG 0-1, and 33% vs 30% high school education level. Testing rates for ES vs mNSCLC cohorts are shown in the table below: prior to treatment initiation, 64% of ES and 83% of mNSCLC pts had at least one biomarker result; and 37% of mNSCLC pts had results for all 9 biomarkers. NGS testing occurred in 37% and 57% of the ES and mNSCLC cohorts respectively. Reasons for not testing included: barriers to ordering (42%, 25%), insufficient tissue (18%, 18%), clinical deterioration/crisis (5%, 12%), and other reasons (37%, 49%), respectively. Conclusions: As more genomic alterations are identified in NSCLC, we observed that many pts do not get full genotyping prior to treatment, and biomarker testing remains of utmost importance. Further analyses by distinct stages (e.g. LA), histology, social determinants, utilization of targeted therapies, and other reasons for not testing will be performed. These data will be used to evaluate future prospective interventions for MYLUNG, to help improve comprehensive biomarker testing for NSCLC. [Table: see text]
CD57+CD8+ T cells and response to PD-1/PD-L1 blockade in patients with NSCLC.
Authors: Jianya Zhou, Wenjia Sun, Xun Zeng, Jing Zheng, Jingjing Qu, Nan Jiang, Jianying Zhou
Journal: Journal of Clinical Oncology (2023)

e21189 Background: Immune checkpoint inhibitors (ICIs) are currently widely used and have made significant advances in the treatment of patients with advanced non-small cell lung cancer (NSCLC). Despite available biomarker stratification, clinical responses vary. Thus, potential biomarkers for identifying patients who will benefit from the immunotherapy are urgently needed. Methods: We applied mass cytometry (CyTOF) to deeply analyze the association of cell subpopulations in PBMC before and after single-agent immunotherapy with clinical outcomes in advanced NSCLC. We then performed flow cytometry of peripheral blood and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) of tumor samples to validate our conclusion. In addition, RNA sequencing (RNA-seq) was performed to explore the mechanism of the ICIs treatment efficacy of NSCLC. Results: In a prospective cohort (n = 20), high CD57+ CD8+ T cell proportion in PBMC detected by CyTOF was associated with good response ( p= 0.014) in advanced NSCLC patients. The result was confirmed in an independent, prospective cohort (n = 30) using flow cytometry, and the specificity and sensitivity of flow cytometry was then assessed in this cohort. CD57+CD8+ T cell proportion, as determined by flow cytometry, successfully stratified responders and non-responders to ICIs ( P&lt; 0.001). We also confirmed this result in FFPE samples (n = 31) ( p= 0.004). In addition, transcriptomic differences between CD57+CD8+ T cells and CD57-CD8+ T cells were found performed by RNA sequencing (RNA-seq). Conclusions: Our results suggest that CD57+CD8+ T cell proportion may serve as a predictive value of response to PD-1/PD-L1 checkpoint blockade. Further validation in additional NSCLC cohorts is warranted.
Final overall survival and biomarker analyses of CHOICE-01: A double-blind randomized phase 3 study of toripalimab versus placebo in combination chemotherapy for advanced NSCLC without EGFR/ALK mutations.
Authors: Jie Wang, Zhijie Wang, Lin Wu, Baolan Li, Ying Cheng, Xiaoling Li, Xicheng Wang, Liang Han, Xiaohong Wu, Yun Fan, Yan Yu, Dongqing Lv, Jianhua Shi, Jianjin Huang, Shaozhang Zhou, Baohui Han, Guogui Sun, Qisen Guo, Youxin Ji, Xiaoli Zhu
Journal: Journal of Clinical Oncology (2023)

9003 Background: Toripalimab in combination with chemotherapy showed significant improvement over chemotherapy alone in progression-free survival (PFS) and overall survival (OS) as first-line treatment of advanced NSCLC at the final PFS analysis of the CHOICE-01 study (NCT03856411). Here we report the final OS analysis. Methods: Patients (n=465) with treatment-naïve, advanced NSCLC without EGFR/ALK mutations were randomized 2:1 to receive toripalimab 240 mg (n=309) or placebo (n=156) in combination with chemotherapy for 4-6 cycles, followed by maintenance toripalimab or placebo plus standard care until disease progression, intolerable toxicity, or completion of 2 years of treatment. Patients from the placebo arm were actively crossed-over to receive toripalimab upon disease progression. The primary endpoint was PFS. The secondary endpoints included OS and safety. Results: By the cutoff date of August 31, 2022, when 283 events triggered the final OS analysis, the median survival follow up was 19.4 months. A significant improvement in OS was observed for the toripalimab arm over the placebo arm: HR=0.73 (95% CI: 0.57-0.93), two-sided p=0.0108, median OS 23.8 vs 17.0 months. A consistent effect on OS, favoring the toripalimab arm, was observed all PD-L1 expression subgroups. The OS benefit is greater in non-squamous NSCLC, HR=0.50 (95% CI: 0.36-0.70), median OS 27.8 vs 15.9 months, whereas no significant difference was found in the squamous subgroup (mOS 19.6 vs 18.1 months) despite a significant PFS improvement. The squamous subgroup had a high 70% crossover rate. No new safety signal was identified since the interim report. The incidence of Grade ≥3 adverse events (AEs) (78.9% vs 82.1%) was similar between the two arms. AEs leading to discontinuation of toripalimab/placebo (14.3% vs 3.2%), fatal AEs (5.5% vs 2.6%), and immune-related (irAEs) (50.6% vs. 21.2%) were more frequent in the toripalimab arm. Whole exome sequencing results indicated patients with mutations in the FAK-PI3K-Akt pathway achieved significantly better OS from the toripalimab arm. Conclusions: The addition of toripalimab to chemotherapy in patients with advanced NSCLC provided significant OS benefit than chemotherapy alone with a manageable safety profile. These results support the use of toripalimab with chemotherapy as 1 st line therapy for advanced NSCLC patients without EGFR/ALK mutations. Clinical trial information: NCT03856411 .